1. Introduction
This invention relates to derivatives of cephalosporin and more particularly, to oxygen analogs of 7-aminocephalosporanic acid and biologically active derivatives thereof.
2. Description of the Prior Art
Following the discovery of the penicillins and their synthesis, perhaps one of the most important advances in medical research was the discovery of the cephalosporin antibiotics and their use in clinical medicine. The cephalosporin antibiotics, though not penicillins, have a structure quite similar to the structure of the penicillins and the two can be coproduced in the fermentation of a cephalosporium organism. Because of this similarity in structure and a similarity in chemical reactivity, considerable research has been devoted to the formation of derivatives of cephalosporins using, to a large extent, chemical reactions useful for the formation of penicillin derivatives. For example, 7-aminocephalosporanic acid (7-ACA) may be obtained by mild acid hydrolysis of Cephalosporin C. The 7-ACA compound is then available for formation of a multitude of derivatives. For example, reacylation of 7-ACA with phenylacetyl chloride gives a derivative that has antibacterial activity approximately 100-fold greater than Cephalosporin C. Many other reactions of the amino group of 7-ACA are known and reported in the literature. Thus, acyl groups, isocyanates, isothiocyanates, halogen compounds, methylisoureas, ethylene oxide, ethylene imine and the like have been introduced into the 7 -amino group of 7-ACA to form both biologically active and biologically inactive derivatives.
In addition to the above, there have been reactions of both the .beta.-lactam ring system and the dihydrothiazine ring system of the cephalosporins. For example, with regard to the .beta.-lactam ring system, C-7 epimers may be formed by treatment of cephalothin sulfoxide with triethylamine in refluxing chloroform. With regard to the dihydrothiazine ring system, there is the possibility of reaction of the double bond, the C-3 substituents and the carboxyl group to form a vast number of derivatives.
Reactions of the cephalosporins, as described above, are reported in part by R. B. Morin and B. G. Jackson, "Chemistry of Cephalosporin Antibiotics", Progress in the Chemistry of Organic Natural Products XXVIII, Wein, Springer-Verlag, 1970.
For brevity, the commonly accepted abbreviation "7-ACA" will be used for the term 7-aminocephalosporanic acid throughout the balance of this specification.